Acetaminophen is a typical antipyretic and analgesic agent which is used frequently instead of aspirin. However, liver toxicity of acetaminophen is recently on the rise as intensive side effect, and has been reported in many articles. The high dose administration of that induces acute liver toxicity. And especially to the patient of alcoholic liver dysfunction, a infant and indeed even a normal healthy person in the case of long-time multiple dosing, it is known that the usual dose administration of acetaminophen also induces widespread liver toxicity and can induce ophthalmic disease such as cataract. Besides, it is worried that a normal healthy person can get liver toxicity induced by acetaminophen because a modern usually takes much alcoholic drink for the release of stress coming from his place of work, etc. Acetaminophen administrated at the condition of liver function weakened by alcohol may induces severe liver toxicity with acceleration effect, and may bring about the retardation of recovery from hangover.
It gets known that the liver toxicity of acetaminophen related to medicines administered together. Alcohol and medicines of barbital family, representatively, increase severely the liver toxicity of acetaminophen through the liver enzyme induction. Especially, it was reported that only usual dose administration of acetaminophen induced a pathological change of liver cell in an alcoholic poisoning person as well as high dose administration of acetaminophen after drinking of alcohol induces severe liver toxicity (J. Biol. Chem., 271(20), 12063; Biochem. Pharmacol., 50(11), 1743; Gastorenterol., 109(6), 1907; Hapatol., 22(3), 767). At low dose, only about 2% of acetaminophen is eliminated as unmetabolized form, and most of that is eliminated as inactive metabolites of sulfonated form (20.about.30%), glucuronic acid conjugation (45.about.55%), and cysteine and mercaptouric acid conjugation (15.about.55%). However, liver enzyme induction agent such as alcohol and barbital, and acetaminophen of high dose increase the activity of cytochrome P-450 in liver cell and bring about production of intensive alkylation agent, that is, active metabolite N-acetly-p-benzoquinoneimine (NAPQI) as well as main metabolite, that is, inactive metabolite. NAPQI produced is inactivated through the conjugation with glutathione, but if the glutathione is depleted, NAPQI binds with --SH group of cell protein and, therefore, induces liver toxicity through alkylation or oxidation.
The agents that can alleviate liver toxicity of acetaminophen are chemicals such as cysteamine, methionine, cysteine, dimethylmercaptol, selenium, tocopherol, ascorbic acid, etc. They can alleviate liver toxicity at various efficacy range of acetaminophen. These chemicals have antioxidation effect commonly and it is proposed that liver toxicity of acetaminophen is alleviated through these antioxidation effects. However, it is known that butylhydroxytoluene, butylhydroxyanisol, etc., which are the representative antioxidants and food additives, increase liver toxicity of acetaminophen and until now the relation of the antioxidation process and the alleviation effect of liver toxicity of acetaminophen did not become clear. Recently, it is concerned about each action mechanisms of such chemicals. In said chemicals having antioxidation effect, thiol compounds (having --SH group) such as methionine, cysteamine, cysteine, dimethylmercaptol, etc. act as precursor of glutathione, and it is known that they can be used for prevention and treatment of liver toxicity of acetaminophen. These thiol compounds alleviate the liver toxicity of acetaminophen by producing glutathiones which conjugate and convert NAPQI, active metabolite of acetaminophen, into inactive metabolite.
Until now many studies, for example, patents such as WO 9,408,628, U.S. Pat. No. 4,314,989, etc. have been performed to alleviate the liver toxicity of acetaminophen. Said patents show that thiol compounds such as diarylsulfone, diarylsulfide, diarylsulfoxide, acetylcysteine, methionine sulfoxide, etc. are efficacious for prevention and treatment of liver toxicity of acetaminophen.
Aspartic acid is the medicine having the promotion effect of alcohol metabolism and facilitates the alcohol metabolism through connecting to Malate-Aspartate Shuttle of liver cell and correcting the ratio of NAD and NADH, which are coenzyme of alcohol metabolism. Alcohol is degraded to acetaldehyde by alcohol dehydration enzyme in existence of NAD.sup.+, which is cofactor, or by microsomal ethanol oxidizing system (MEOS) and degradation enzyme of peroxisome in existence of NADPH. Acetaldehyde produced is also metabolized to acetic acid, as a final product, by aldehyde dehydration enzyme in existence of NAD.sup.+. However, in the case of taking much alcohol, alcohol degradation enzyme is saturated and, therefore, overall alcohol metabolism becomes slow and the blood concentrations of alcohol and aldehyde increase. Especially due to the saturation of aldehyde dehydration enzyme aldehyde, which induces extensive side effects, is not able to be metabolized into acetic acid and is accumulated continuously. The acetaldehyde causes, what is called, hangover state by inducing nausea, vomiting, headache as well as liver toxicity. Moreover, in the accumulation state of acetaldehyde acetaminophen administration increases the side effect of acetaldehyde as well as liver toxicity of acetaminophen. At this point, aspartic acid acts NAD.sup.+ production by connecting to Malate-Aspartate Shuttle and, therefore, does not make only alcohol degradation but also acetaldehyde metabolism possible through metabolizing acetaldehyde, which is a hangover-causing material, to acetic acid. Therefore, aspartic acid is efficacious to prevention and removal of hangover state.